Molecular glues that facilitate RAS binding to PI3Kα promote glucose uptake without insulin

While exploring strategies to control blood glucose concentrations in diabetes, we identified so-called molecular glues D223 and D927 that promote glucose uptake in the absence of insulin. They act by increasing the binding affinity of phosphoinositide 3-kinase α (PI3Kα) catalytic subunit p110α to canonical small guanosine triphosphatase RAS proteins and to RRAS, RRAS2, and MRAS by three orders of magnitude. The compounds bind to the RAS-binding domain of p110α, stabilizing the secondary structures of the PI3Kα in a RAS-binding conformation and forming direct interactions with RAS residues tyrosine-40 and arginine-41. In vivo, D927 mimicked the effects of insulin: It rapidly lowered blood glucose concentrations, enhanced glucose metabolism in normal and Zucker fatty rats, and improved hyperglycemia in models of type 1 and type 2 diabetes, even in insulin-deficient diabetic animals.

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Publication Details

Journal
Science
Published
2025-07-24
DOI
https://doi.org/10.1126/science.adr9097
Citations
8
Primary Topic
PI3K/AKT/mTOR signaling in cancer
Type
article
Field-Weighted Citation Impact
6.45
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article

Molecular glues that facilitate RAS binding to PI3Kα promote glucose uptake without insulin

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Science
PI3K/AKT/mTOR signaling in cancer
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article

Molecular glues that facilitate RAS binding to PI3Kα promote glucose uptake without insulin

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article en
8 citations

Abstract

While exploring strategies to control blood glucose concentrations in diabetes, we identified so-called molecular glues D223 and D927 that promote glucose uptake in the absence of insulin. They act by increasing the binding affinity of phosphoinositide 3-kinase α (PI3Kα) catalytic subunit p110α to canonical small guanosine triphosphatase RAS proteins and to RRAS, RRAS2, and MRAS by three orders of magnitude. The compounds bind to the RAS-binding domain of p110α, stabilizing the secondary structures of the PI3Kα in a RAS-binding conformation and forming direct interactions with RAS residues tyrosine-40 and arginine-41. In vivo, D927 mimicked the effects of insulin: It rapidly lowered blood glucose concentrations, enhanced glucose metabolism in normal and Zucker fatty rats, and improved hyperglycemia in models of type 1 and type 2 diabetes, even in insulin-deficient diabetic animals.

ScienceVol. 389(6758)
University of California, San Francisco (US), Daiichi-Sankyo (Japan) (JP), Frederick National Laboratory for Cancer Research (US), National Cancer Institute (US), UCSF Helen Diller Family Comprehensive Cancer Center (US)
Good health and well-being
Openalex Percentile: Top 3%
PI3K/AKT/mTOR signaling in cancer
6.45
DOISourceOpenAlex
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